The retina is among the most highly vascularized and metabolically active tissues in the body. Like the central nervous system of which it is a part, it is also susceptible to ischemic injury. Degenerative diseases of the eye often have either hemodynamic consequences or causes, though many mechanisms remain unknown. Improved blood flow imaging diagnostics for retinal circulation and perfusion can aid the detection and management of eye disease, and research on retinal function and metabolism.
The retinal circulation apparent in images generated by scanning laser ophthalmoscopy (SLO) originates from the central retinal artery that passes through the optic nerve head before branching into superior, inferior, nasal, and temporal arteries, into many smaller vessels, and ultimately, into capillary networks. The underlying choroidal vessels and choriocapillaris beneath the retinal pigment epithelium (RPE) account for approximately 90% of the blood flow nourishing the retina. While rapid flow in the retinal vascular tree is readily visualized, the perfusion of the retina through the micro-vasculature on both sides of the RPE is critically important. For eye diseases such as diabetic retinopathy, macular degeneration, and glaucoma, these structures exhibit early flow defects or the growth of new vessels triggered by metabolic distress and other factors.
Both the retinal and choriodal vessel diameters range from ˜5 μm (in the retinal capillary bed and choriocapillaris) to ˜0.4 mm (major vessels). Flow rates range from local quasi-isotropic perfusion rates of tens of μm/s in the capillaries to pulsatile values of several cm/s in the arteries. This range of dimensions and flow parameters presents an extremely demanding diagnostic problem in terms of spatial resolution, field of view, and dynamic range. Dye angiography is a powerful tool for global visualization of retinal vessel topology, occlusions and, uniquely, leakage. Fluorescein and indocyanine green (ICG) dyes have different properties that emphasize different aspects of vascular physiology. However, at present, early transit phase dye angiography of both types can provide at best only a fleeting glimpse of dynamic flow characteristics. Few methods accomplish dynamic blood flow imaging non-invasively (i.e., without dyes); fewer still quantitatively; and none with the wide field, high resolution, and dynamic range to characterize retinal hemodynamics globally. Reproducibility is essential for longitudinal studies, and also for sensitive detection of functional correlations with local neuronal activity or pharmacological effects. In short, despite decades of research and the introduction of several advanced systems for measurement of blood flow, retinal blood flow Doppler imaging diagnostics have not yet achieved the clinical prominence that retinal biology would seem to justify.
When imaging biological tissues with lasers, the phenomenon of speckle is a necessary consequence of coherent illumination. The superposition of scattered photons for an extended source produces a net wavefront at the receiving aperture that varies in amplitude and phase. For imaging instruments whose signal-to-noise ratio is well above the shot noise limit, speckle can be a dominant source of the large fluctuations in apparent reflectivity and the granularity in captured images (depending on the degree of confocality). A stationary ensemble of scatterers can produce a stationary speckle pattern. Such variations are not intrinsic reflectivity variations, and so from a static imaging viewpoint, can be regarded as noise, with concomitant reduction of image contrast and spatial resolution. When particles in motion are of interest, however, the scattered light also has imposed Doppler frequency shifts dependent upon the scattered wave-vectors and velocities of the particles. The frequency content of the imaged light can be measured and velocities inferred. In this sense, in living biological tissue, speckle can be regarded as a contrast agent enabling the visualization of dynamic processes.
Speckle interferometry and its related imaging technologies can exploit the temporal characteristics of fluctuations that contain information about the motion of particles within an optically probed or imaged volume. The DC or zero frequency component of the temporal spectrum at an image pixel can include the time-averaged power during the observation, and therefore asymptotically, the intrinsic incoherent reflectivity or the “speckle-free” image. The AC component can include quantitative measures related to particle number density and velocity distributions within the probed volume element (voxel).
Multiple scatterers within image volumes can give rise to some complex and often counter-intuitive characteristics for Doppler signals. Red blood cells are strongly forward scattering in the near infrared, and most of the scattered light per interaction falls within a sharply peaked cone with ˜6 deg half angle. The result can be a distribution of Doppler frequencies even for a single well-defined velocity vector. Direct backscatter from flowing blood is generally a weak component of the signal, so the usual conception of the Doppler signal can be misleading. Mainly, light forward scattered by blood is subsequently backscattered by denser tissues. This dual-scatter enables velocities perpendicular to the incident beam to contribute to the Doppler signal, but can result in Doppler signals that have ambiguous spatial origin. At the largest scales of arteries and veins in, fore example, the retina, the velocities are large with a single well-defined direction. At the capillary or perfusion scale, velocities are small, perhaps with multiple flow directions within a single voxel. Multiple light scattering can cause these fine scales to lose contrast in flow images based upon Doppler frequency shifts. However, the total Doppler signal power per unit of imaged moving tissue volume is approximately preserved.
Some of the first applications of Doppler methods to retinal blood flow diagnostics used a single laser beam that was focused on the retina, and the flow in retinal vessels and capillary perfusion were found to be measurable and quantifiable with laser Doppler flowmetry. Later, two imaging approaches emerged using CCD fundus images (laser speckle imaging or flowgraphy) and flying-spot confocal SLO devices such as scanning laser Doppler flowmetry (e.g., Heidelberg Retinal Flowmeter, HRF). Concurrently, color Doppler optical coherence tomography (OCT) or optical Doppler tomography (ODT) was found to provide local anatomical detail with velocity information when blood moves parallel to the probe beam. Such measurements can be difficult to interpret for complex vessel topology. Most recently, the remarkable capabilities of high-speed, spectral domain ODT (SDODT) for blood flow measurement have been described. The improvement in retinal flow visualization has been considerable. However, all of these approaches trade resolution, field-of-view, dynamic range, velocity component sensitivity and Doppler frequency range against scan speed and system noise. The motion of the eye, the cardiac and respiratory rhythms and other effects render the lowest frequencies virtually uninterpretable. Low data rates and high-frequency aliasing render the highest flows inaccessible and/or inaccurate.
Many scanning imaging technologies can suffer from practical limitations in the living eye as well at eye-safe light levels, e.g., scan areas or volumes and scan times are restricted by eye motions or other registration issues that corrupt data and are generally not correctable by post-processing. In other words, at present, almost all scanning imaging operations must fit within a relatively brief window in time—for example, on the order of a second, approximately the mean time between small saccades. This severely impacts the size of the measured fields and the trade-offs that need to be made in data quality. The resulting difficulties of flow quantification, velocity range, sensitivity, dynamic range, and field of view have not yet been overcome by the prior art, especially for correlation of precise information about local anatomical features with the wide-field angiographic data familiar to clinicians.